2, 2-diphenyl-3-methyl-4-chlorobutyronitrile and processes for preparing the same



Patented Mar. 9, 1954 2,2-DIPHENYL -3- METHYL 4 CHLORO- BUTYRONITRILE AND PROCESSES FOR PREPARING THE SAME Earl M. Chamberlin and Max Tishler, Westfield, N. J., assignors to Merck & 00., Inc., Railway, N. J., a corporation of New Jersey N Drawing. Original application April 9, 1949, Serial No. 86,596. Divided and this application July 25, 1951, Serial No. 238,576

6 Claims. 1

This invention relates o the manufacture of compounds possessing analgesic and anesthetic action In particular, it concerned with an improved synthetic method for preparing 2,2-diphenyl-3-methyl-4-dimethylamino-butyronitrile and with novel chemical compounds useful as intermediates in the preparation of this compound. 2,2-diphenyl-3-methyl -4- dimethylamino-butyronitrile is itself an important intermediate in the synthesis of isoamidone, l-dimethylamino-2-methyl 3,3 diphenyl-hexanone-4 and salts thereof. Isoamidone and its salts possess analgesic action and may be used as substitutes for morphine.

This application is a division of our co-pending application Serial No. 86,596, filed April 9, 1949, now Patent No. 2,607,794.

2,2-diphenyl -3 methyl 4 dimethylamino-butyronitrile has been prepared previously by reacting 1-dimethylamino-2-chloropropane with di phenylacetonitrile as described by Schultz et al. (J. A. C. S. 69, 188-189, Jan. 1947). As pointed out by these workers, however, when 2,2-diphenyl 3 methyl-d-dimethylamino butyronitrile is prepared by this procedure, there is obtained, at the same time and mixed with this compound, the isomeric nitrile 2,2-diphenyl-4 methyl-4-dimethylamino-butyronitrile. The latter nitrile isomer constitutes an unwanted lay-product since it cannot be converted to isoamidone.

Moreover, the preparation of isoamidone directly from the mixture of isomeric nitriles has not proven feasible. In order to prepare isoamidone, it has therefore previously been necessary to isolate the desired 2,2-diphenyl-3-meth- 3 1-4dimethylamino-butyronitrile from the mix ture and this has necessitated a complicated separation procedure which results in a considerable loss of the desired isomer.

It is now discovered that the desired 2,2-diphenyl-3-methyl 4 dimethylamino-butyronitrile can be prepared by a novel process which does not produce any of the unwanted isomeric nitrile. This improved method thus eliminates the loss due to formation of the by-product isomer and at the same time avoids the need for a complicated separation procedure with its attendant losses of the desired isomer. 7

novelprocess is conducted as follows: propylene chloroh-ydrin (compound 1 below) is reacted with an organic sulfonyl chloride (compound 2) to produce the corresponding l-methyl-2-chloroethyl-sulfonate (compound 3). This compound is then treated with the reaction prodnot of diphenyl acetonitrile' and sodamide to produce 2,2 aiphenyi-amanyheohiombnyrotn trile (compound 4) Which is reacted with di'rnth ylainine to form 2',2-dipheny1- 3 metny1=g=dimethylamino-butyronitrile (compound 5) These reactions may be chemically represented as follows:

USUZR e5 (CaH5)2C-CHCH2N(CH3)2 (ono irii (chore-enema Ci (3H3 ON, 9H8

The organic su1rony1 chloride employed in the foregoing reaction can be either an aromatic sulfonyl chloride such as p-to1uene sulfo'nyl chloride, benzene'sulfonyl chloride the like. or an aliphatic sulfonyl chloride such as methane sulfonyl chloride.

The reaction between propylene ohlo'rohyaria and the aromatic sulfonyl chloride is ordinarily carried out in the presence of pyridine, preferably at a temperatiireof approximately 0f G. U cor these conditions, the reaction is usuaiiy om j after a reaction period of 1 to 3 days. The 'pyri dine hydrochloride, formed are bY-l rodut' or this reaction, ordinarily precipitates and is' separated from the reaction mixture by filtration. The filtrate is then mixed with water and an organic water-immiscible solvent such as ether, chloroform, benzene, toluene, Xylene and tlie'like. The ether layer is separated and washed with an aqueous solution of a mineral acid such as hy'E- drochloi'ic acid, hydrobromic acid, sulfuric acid, and the like, and then with water. The ethereal solution is dried and evaporated to dryness under reduced pressure to produce, in the form or an oily residue, the corresponding 1-met1iy1-'2'=cn1oroethyl organic suironote, as for example i-nieth yl-2-chloroethyl-p-toliienesulfonate, 1 meth r 2 -chloroethyl howman-roasts, '1 methyl 2 chloroethyl-inethane-sulfonate, and the like.

This product is ordinarily purified by tr atment with aqueous pyridine to convert the residual in garlic su1foriyl chloride to an acid. The resisting mixture is treated with an or anic womanmiscible solvent and aqueous hydrochloric ac d and the layers are separated. The organic solvent layer is washed first with an aqueous S6111 tion or a mineral acid and then with water: the organic l yer isthen further purified, if desired, 15y washing with an aqueous aikau'ne stirs tion such as aqueous sodium hydroxide, aqueous potassium hydroxide, aqueou ammonium hydroxide, and the like, and again with water. The solvent layer is then dried and evaporated to dryness in vacuo to produce the desired l-methyl-2- chloroethyl organic sulfonate as a clear light yellow oil which is ready for use in the reaction with diphenyl acetonitrile.

The above procedure can be varied by using a considerable excess of pyridine in the reaction between the organic sulfonyl chloride and propylene chlorohydrin. Under these conditions, there is an excess of pyridine present after the pyridine hydrochloride is removed by filtration. The addition of water at this point followed by a standing period results in complete hydrolysis of sulfonyl chloride- The step of purifying the first oily residue is eliminated since the l-methyl- 2-chloroethyl organic sulfonate formed at this stage is of satisfactory purity for employment in the subsequent reaction step.

The l-methyl-Z-chloroethyl organic sulfonate is treated with the reaction product of diphenylacetonitrile and sodamide. The diphenylacetonitrile is mixed with an equivalent molar quantity of sodamide and a liquid hydrocarbon, preferably a liquid having a boiling point of at least about 110 C., such as xylene, toluene, or liquid petrolatum. The resulting mixture is heated and stirred until at least about 95% of the theoretical amount of ammonia has been liberated, which ordinarily requires between about 3 and 5 hours. The reaction is ordinarily carried out at a temperature of about 105-1l0 C. under reflux and in the presence of a nitrogen atmosphere.

This reaction mixture is then cooled to between about '70 and 90 C. and the l-methyl-2- chloroethyl organic sulfonate is added thereto rapidly, preferably keeping the temperature below about 90 C. The resulting mixture is then heated under reflux until the reaction is substantially complete, which ordinarily requires about 14 to 18 hours. The reaction mixture is then mixed with water, and the organic layer is separated, washed with water and dried. The organic layer is evaporated to dryness to produce a crude product which may be used, if desired, in the subsequent reaction with dimethylamine. The crude product can be purified by distillation in vacuo to produce substantially pure 2,2 diphenyl 3 methyl-4-chloro-butyronitrile (compound 4).

As pointed out above, the nitrile product prepared in this way consists only of the desired 2,2 diphenyl 3 methyll-chloro-butyronitrile uncontaminated with any isomeric product. This is clearly important in view of the fact that when diphenyl acetonitrile is reacted with 1-dimethylamino-2-chloropropane (as described in the Schultz article referred to on page 2) the product contains both 2,2-diphenyl-3-methyl-4- dimethylaminobutyronitrile and 2,2-diphenyl-4- dimethylaminovaleronitrile.

An extremely important and unexpected feature of this sodamide condensation is that the reaction proceeds preferentially with the elimination of the organic sulfonyl group attached to the middle carbon atom of the propane moiety, thus producing the desired 2,2-diphenyl-3- methyl 4 chloro butyronitrile. Inasmuch as alkyl halides are known to alkylate readily under the same conditions, it might have been expected that the reaction would have taken place with the elimination of the chlorine atom attached to the end carbon atom of the propane moiety thus forming the unwanted 2,2-diphenyll-(organic-sulfonyl) -valeronitrile. The formation of this compound, in other than small amounts, would make the reaction impractical.

The 2,2-diphenyl-3-methyl-4-ch1oro butyronitrile is then reacted with substantially anhydrous dimethylamine. Small amounts of water are not harmful, but larger amounts result in a heterogeneous mixture of reactants. It is therefore preferred to conduct the reaction under substantially anhydrous conditions. It is ordinarily desired to employ an excess of dimethylamine in the reaction. Since dimethylamine is a gas at room temperature, it is convenient to mix the reactants together at a temperature below about 7 C. The mixture of re actants is then heated in a pressure vessel to a temperature of approximately -150 C. Under these conditions, the reaction is ordinarily complete in approximately 48 hours.

If desired, the reaction can be carried out in the presence of a solvent for the reactants, such as ethyl alcohol, and at a temperature of about 100-150 C. It has been found, however, that the presence of an organic solvent, such as ethanol, tends to lower the yield. It is ordinarily preferred, therefore, to carry out the reaction utilizing dimethylamine and 2,2-diphenyl-3- methyl-4-chloro-butyronitrile as the sole components, and to conduct the reaction at the higher temperature of C. employing the longer reaction period (48 hours), since these conditions have been found to result in the obtainment of a higher yield than that obtainable when the reaction is carried out in the presence of a solvent.

A mixture of water and an organic waterimmiscible solvent such as ether, chloroform, benzene, toluene, xylene, and the like, is then added to the reaction mixture and the organic solvent layer is extracted with an aqueous solution of a mineral acid such as hydrobromic acid, sulfuric acid, and the like. The aqueous acid extracts are then neutralized with an inorganic base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide and the like, and the aqueous alkaline solution extracted with an organic water-immiscible solvent. The organic solvent extracts are combined and evaporated to dryness in vacuo to produce crude 2,2-diphenyl-3-methyl-4-dimethylamino-butyronitrile. Since this material is obtained by reaction of dimethylamine with the single isomer, 2,2-di phenyl-3-methyl 4 chloro butyronitrile, this product is likewise uncontaminated with any isomeric nitrile material. The crude 2,2-diphenyl-3-methyl-4-dimethylamino-butyronitrile can be used, without further treatment, for the production of isoamidone. It may be purified as follows: The crude material is dissolved in ether or other organic solvent, the ether solution is saturated with dry hydrogen chloride gas, and the amine hydrochloride, which precipitates, is recovered by filtration and recrystallized from absolute ethanol to produce substantially pure 2,2-diphenyl-3-methyl-4-dimethylamino-butyronitrile hydrochloride.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given by way of illustration and not of limitation.

Example 1 In 79 gms. of pyridine were suspended 190.6 arms. of p-toluene sulfonyl chloride, and the mixemerges 5. ture was cooled too C. Tothissuspension', 9536 grns. of propylenechlorohydrin were added; slowly, with stirring, keeping the temperature at C. Stirring at 0 C.', was continued for 3 hours. The reaction mixturewas allowed to stand in an icebox' for 24 hours, and was then stirred at room temperature for about 40 hours.-

Pyridine hydrochloride; which had precipitated; was removed by filtration; and thefiltrate' was diluted with ether and water. The two layers were separated, and the ethereal layer was washed successively with 2.5 N hydrochloric acid and water. The ethereal solution was dried and concentrated to dryness in vacuo.

To the oily residue, 79 gms. of pyridine and cc. of water were added; and'the solution wasallowed to stand 1 hour, to convert residual ptoluene sulfonylchloride to the acid; Ether'and hydrochloric acid were added, and the-layers were separated. The ethereal layer was washed successively with hydrochloric acid and water. The ethereal solution was dried and concentrated to dryness in vacuo. There was obtained a residue of 203.1 gms. (81.3%) of l-methyl-Z chloroethyl p-toluene sulfonate which was obtained in the form of a clear, light-yellow oil.

A portion of this oil was distilled; it boiled at 106-118 C./0.1-0.25 mm. Analysis.Calcd for CroI-IwOxClSZ C, 48.29; H, 5.27; Cl, 14.26; Found? C, 48.76; H, 4.64; Cl, 13.9.

Example 2 In 158.2 guns. of pyridine were suspended 190.6 gms. of p-toluene sulfonylchloride, and the mixture was cooled to. 0 C. To this suspension, 9416 gins. of propylene chlorohydrin were added slowly, with stirring, keeping the temperature at 0 C. Stirrin at 0 C. was continued for 1 hour.

The reaction mixture was allowed to stand in In 156.2 grns. of pyridine were suspended 176.6 ems. of benzenesulfonyl chloride, and the mixture was cooled to 0 C. To his. suspension, 94.6 gms. of propylene chlorohydrin were added slowly, with stirring, keeping the temperature at 0 C. Stirring at 0 C., continued for 1 hour. The reaction mixture was allowed to stand in an icebox for about 42 hours, and was then stirred at room temperature for about 24 hours.

Pyridine hydrochloride, which had precipitated, was removed by filtration. To the filtrate were added 10 cc. of water, and the solution was allowed to stand 1 hour. Ether and hydrochloric were added, and the layers were separated. The ethereal layer was washed successively with hydrochloric acid, water, sodium hydroxide, and water. The ethereal solution was dried and distilled in vacuo. There was obtained 205.5 g-ms. (37.2%) of 1-methyl-2-chloroethyl-benzenesulfonate, boiling point 105-106 C./0.1 mm. Analg- 6. sis;-Calod; for Gel-111030182: C, 4.5.66; H; $.71; 01; 15.04; Found: 0,146129; H, 4194;. G1, 1435.

Example 4 In;79.1 gmsuoi. pyridinewere suspended 57.3 gms. ofimethanesulionyl chloride, andthe mixture wascooledto 0C. To'this suspension, 47.3 gins; of'propylene chlorohydriirwere added slowly withstirring, keepingthe temperature at 0 C. Stirring at 0f C: wascontinuedfor 1, hour. The reaction mixture was allowedito stand; inanicebox overnight, and was then stirred at room temperature for aboutfiehours.

The precipitate. of pyridine hydrochloride was removed by filtration. To.the filtrate was added 8 cc. of water, and the solution was stirredfor 1 hour. Benzene. and hydrochloric acid were added and the layers. were separated. Thebenzene layer was washed, successively withhydrochloric acid, water and sodium hydroxide and water. The benzene solution was dried and distilled, in vacuo. There was, obtained 65' gms. (75.5%) of. 1-methyl-2-chloroethyl-methanesul innate, boiling point 76.54 7 C./0.4'1 mm. Analysia CaloZdfOr. CAHsiOsCIS: C, 27.76; H, 5.26; Cl, 20.54; Found: C; 28.19; H, 5.37; Cl, 20.81.

Example- 5' To 35.4 gms. of, sodamide under nitrogen, a solution of 175.5 gins. of diphenylacetonitrilein 1200 cc. of toluenewasadded rapidly; The mixture Was heated with stirring to 106 C.,, and maintained at this temperature for about 3% hours.

The reaction mixture was then cooled to. 70 C., and 22.7 gins. of 1-methyl-2-chloroethyl-ptoluenesulfonate were added rapidly, keeping the temperature below C. The mixture was then heated at reflux for about 13 hours, cooled to 70 0., and 500 cc. of Water were added. The organic layer was separated, washed with water, and dried. It was then distilled in vacuo. There was obtained 140 gms. (57%) of 2,2-dipheny1-3- methyl-l-chloro-butyronitrile, boiling point 154- 160 C../0.2.mm.. AnaZysis.--Ca1cd for C17Hl6NC1Z C, 75.68; H', 5.98; N, 5.19;,Found: C, 75.68; H, 5.90; N, 5.33.

Example 6 To 7.9 gms. of sodamide-and cc.,of toluene, under. nitrogen, a. solutionof 3.8.6, sins. of diphenylacetonitril'e in.30'0 cc. of toluene was added rapidly. The mixture: was heated with stirring to C, and: maintained at this temperature for about. 3 hours; The: reaction mixture Wasthen cooled; to: 65 C.,. and 472. gms. of: 1-methyl-2- chloroethyl-benzenesulfonate were added rapidly, keeping the temperature below 85 C. The mixture was then heated at reflux for about 18 hours, cooled to 70 C. and 500 cc. of water were added. The organic layer was separated, washed with water and dried. It was then distilled in vacuo. There was obtained 37 gms. (69%) of 2,2-diphenyl-3-methyl-4 chloro-butyronitrile, boiling range 143-150 C./0.17 mm. AnaZysis.-Calcd for CrzHisNClz C, 75.69; H, 5.98; Found: C, 75.71; H, 6.05.

Example 7 To 13.6 gms. of sodamide under nitrogen, a solution of 57.2 gms. of diphenylacetonitrile in 1200 cc. of toluene was added rapidly. The mixture was heated with stirring to 108 C., and maintained at this temperature for about 5 hours.

The reaction mixture was then cooled to 90 C., and 60 gms. of 1-methyl-2-chloroethyl-methane- 7 sulfonate were added rapidly, keeping the temperature below 90 C. The mixture was then heated at reflux for about 14 hours, cooled to room temperature and 500 cc. of water were added. The organic layer was separated, washed with water, and dried. It was then distilled in vacuo. There was obtained 50 gms. (52.7%) of 2,2-diphenyl-3-methyl 4 chloro-butyronitrile, boiling range 116-128 C./0.04 mm. Analysis.- Calcd for C1'1H16NC1: C, 75.68; H, 5.98; N, 5.19; Cl, 13.15; Found: C, 76.06; H, 6.34; N, 4.89; CI, 12.74.

Example 8 In 20 cc. of absolute ethanol were dissolved gins. of 2,2-diphenyl-3-methyl-4-chloro-butyronitrile, and the solution was cooled in a Dry Iceacetone bath. The cold solution was added to cc. of anhydrous dimethylamine, cooled in a Dry Ice-acetone bath. The mixture was then sealed in a bomb tube and heated overnight at 100 C.

The contents of the tube were concentrated to dryness in vacuo, and to the residue was added ether and water. The layers were separated, and the ether layer was extracted with hydrochloric acid. The acid extracts were made alkaline with sodium hydroxide, and were then extracted with ether. The ethereal extracts were dried and concentrated to dryness in vacuo. The residue crystallized on cooling and scratching.

The residue was dissolved in ether and saturated with dry HCl gas. 2,2-diphenyl-3-methyl- 4 dimethylamino butyronitrile hydrochloride precipitated, was removed by filtration, and was recrystallized from absolute ethanol, M. P. 218-220 C. The mixed melting point with an authentic sample of the nitrile hydrochloride was 218-220 C. Comparison of the product with an authentic sample of the nitrile hydrochloride by means of infra-red spectra showed the two compounds to be identical. AnaZysis.-Calcd for C19H23N2C1I C, 72.48; H, 7.36; N, 8.90; Found: C, 72.34; H, 7.24; N, 9.09.

Example 9 To 20 cc. of anhydrous dimethylamine cooled in a Dry Ice-acetone bath were added 20 gms. of 2,2-diphenyl 3 methyl-4-chloro-butyronitrile. The mixture was sealed in a bomb tube and heated at 150 C. for 48 hours.

Ether and water were added to the reaction mixture, and the two layers formed were separated. The ethereal layer was extracted with hydrochloric acid. The acid extracts were neutralized with sodium hydroxide and extracted with ether. The ether extracts were concentrated to dryness in vacuo. There was obtained a residue of 9.8 gms. (47.5%) of 2,2-diphenyl-3-methyl-4- dimethylamino-butyronitrile. This can be purified, if desired, as outlined in Example 8.

Various changes and modifications may be made in our invention without departing from the spirit and scope thereof. Insofar as these changes and modifications are within the purview of the annexed claims, they are to be considered as part of our invention.

We claim:

1. The process which comprises reacting an organic sulfonate of propylene chlorohydrin with the condensation product of diphenylacetonitrile and sodamide.

2. The process of preparing 2,2-diphenyl-3- methyl-4-chloro-butyronitrile which comprises reacting diphenylacetonitrile with sodamide in the presence of a liquid hydrocarbon, and treating the condensation product with an organic sulfonate of the formula:

wherein R is a radical selected from the class which consists of alkyl, aryl, aralkyl and alkaryl radicals.

3. The process of preparing 2,2-diphenyl-3- methy1-4-chloro-butyronitrile which comprises reacting diphenylacetonitrile with sodamide in the presence of a liquid hydrocarbon, and heating the reaction product with l-methyl-Z-chloroethyl p-toluene sulfonate.

4. The process of preparing 2,2-diphenyl-3- methyl-4-ch1oro-butyronitrile which comprises reacting diphenylacetonitrile with sodamide in the presence of a liquid hydrocarbon, and heating the reaction product with l-methyl-Z-chloroethyl benzene sulfonate.

5. The process of preparing 2,2-diphenyl-3- methyl-4-chloro-butyronitrile which comprises reacting diphenylacetonitrile with sodamide in the presence of a liquid hydrocarbon, and heating the reaction product with 1-methy1-2-chloroethyl methane sulfonate.

6. 2,2-diphenyl-3-methyl 4 chloro-butyronitrile.

EARL M. CHAMBERLIN.

MAX TISI-ILER.

References Cited in the file of this patent FOREIGN PATENTS Number Country Date 563,665 Great Britain Aug, 24, 1944 OTHER REFERENCES Dupre et al., J. Chem. Soc., 1949, pp. 500-518. 

6. 2,2-DIPHENYL-3-METHYL-4-CHLORO-BUTYRONITRILE. 